Project Summary I am an academic hematologist passionate about clinical research. My primary goal is to become a successful, independent physician-scientist with expertise in the biology, epidemiology, and evidence-based practice of rare bleeding disorders. More specifically, my long-term research goal is to better define the role of age and age-related conditions in hereditary bleeding disorders, such as von Willebrand disease (VWD). This K23 award will allow me to develop the skills necessary to act as a principal investigator for multicenter clinical research studies, become trained in epidemiological research, and become proficient in the use of bioinformatics to analyze genetic data. I have assembled an outstanding mentorship team, including experts in hematology and epidemiology, to help me achieve these goals. My clinical research activities will be conducted at HCWP and benefit from the excellent research infrastructure. The goal of this proposal is to determine the effect of age on von Willebrand factor (VWF) levels and bleeding risk in patients with type 1 VWD. We will perform a multicenter, cross-sectional study enrolling patients with type 1 VWD, age 18 and older, at participating Hemophilia Treatment Centers (N=7) during clinic visits. Following enrollment, the condensed MCMDM-1 VWD bleeding assessment tool will be administered and blood samples will be obtained. Laboratory tests include VWF antigen (VWF:Ag) level, VWF ristocetin cofactor activity, factor VIII activity, and blood type. An additional blood sample will be obtained for DNA isolation for VWF gene sequencing and analysis. We hypothesize that age is associated with increased VWF:Ag levels and lower condensed MCMDM-1 VWD bleeding scores in patients with type 1 VWD. In addition, we hypothesize that multimorbidity partially explains the association between age and VWF:Ag levels. We also propose that VWF:Ag levels partially explain the association between age and condensed MCMDM-1 VWD bleeding scores. Finally, we expect the effect of age on VWF:Ag levels and condensed MCMDM-1 VWD bleeding scores is weaker among those with a pathogenic VWF mutation. The identification of bleeding risk in elderly type 1 VWD patients is essential for providing appropriate medical care to affected patients. Administering VWD-specific therapy to older type 1 VWD patients with normalized VWF levels may be harmful, placing patients at risk for thrombosis. Thus, investigation into the effect of age on VWF levels and bleeding risk in VWD patients is sorely needed. The results from this study will provide preliminary data for several future R-level independent studies: 1) a longitudinal observational study assessing bleeding risk with age in VWD patients; 2) a clinical trial comparing bleeding and safety outcomes among type 1 VWD patients with normalized VWF levels undergoing invasive procedures randomized to VWD therapy or no VWD therapy; and 3) gene sequencing of biorepository samples to identify candidate non-VWF loci and explore how they interact with the effect of age on VWF levels and bleeding risk. !